chrX-96738591-C-A

Variant names:

• chrX-96738591-C-A
• rs956029682
• NM_006729.5:c.171C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_006729.5(DIAPH2):​c.171C>A​(p.Asp57Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000505 in 1,188,771 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: DIAPH2 NM_006729.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58
• Publications: 0 publications found

Genes affected

DIAPH2 (HGNC:2877): (diaphanous related formin 2) The product of this gene belongs to the diaphanous subfamily of the formin homology family of proteins. This gene may play a role in the development and normal function of the ovaries. Defects in this gene have been linked to premature ovarian failure 2. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

DIAPH2 Gene-Disease associations (from GenCC):

• premature ovarian failure 2A

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3263213).
• BS2: High Hemizygotes in GnomAd4 at 2 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006729.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH2	NM_006729.5	MANE Select	c.171C>A	p.Asp57Glu	missense	Exon 3 of 27	NP_006720.1	O60879-1
	DIAPH2	NM_007309.4		c.171C>A	p.Asp57Glu	missense	Exon 3 of 27	NP_009293.1	O60879-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH2	ENST00000324765.13	TSL:1 MANE Select	c.171C>A	p.Asp57Glu	missense	Exon 3 of 27	ENSP00000321348.8	O60879-1
	DIAPH2	ENST00000373049.8	TSL:1	c.171C>A	p.Asp57Glu	missense	Exon 3 of 27	ENSP00000362140.4	O60879-2

Frequencies

GnomAD3 genomes AF: 0.0000361 AC: 4 AN: 110873 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000611 AC: 1 AN: 163695 AF XY: 0.00

Gnomad AFR exome AF: 0.0000805

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.28e-7 AC: 1 AN: 1077845 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 350009

African (AFR) AF: 0.00 AC: 0 AN: 25187

American (AMR) AF: 0.00 AC: 0 AN: 31297

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18473

East Asian (EAS) AF: 0.00 AC: 0 AN: 29986

South Asian (SAS) AF: 0.00 AC: 0 AN: 50276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40219

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3907

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 833326

Other (OTH) AF: 0.00 AC: 0 AN: 45174

GnomAD4 genome AF: 0.0000451 AC: 5 AN: 110926 Hom.: 0 Cov.: 22 AF XY: 0.0000601 AC XY: 2 AN XY: 33258

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000164 AC: 5 AN: 30565

American (AMR) AF: 0.00 AC: 0 AN: 10363

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3546

South Asian (SAS) AF: 0.00 AC: 0 AN: 2625

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52906

Other (OTH) AF: 0.00 AC: 0 AN: 1508

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00109982), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000718

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.053	D
MutationAssessor	Benign	1.3	L
PhyloP100		3.6
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.31
Sift	Benign	0.58	T
Sift4G	Benign	0.65	T
Polyphen		1.0	D
Vest4		0.35
MutPred		0.28		Loss of helix (P = 0.0033)
MVP		0.91
MPC		0.31
ClinPred		0.17	T
GERP RS		5.6
Varity_R		0.35
gMVP		0.63
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs956029682; hg19: chrX-95993590;